mouse pharmacogenomics
TRANSCRIPT
Towards systematic chemical genomics in mice and humans
Chris Cotsapas PhDDaly Lab
CHGR, MGHMPG, Broad
The shoulders of giants
MGH
Mai Saito
Mari Mino-Kenudson Broad/MPG
Mark Daly
David Altshuler
Supriya Gupta
Jennifer Moran Broad/ChemBio
Stuart Schreiber Broad/BMI
Vamsi Mootha
Joel Hirschhorn
Broad/NT
Robert Gould MIT
Sangeeta Bhatia
Salman Khetani
Steve Katz Broad/Cancer
David Thomas
Todd Golub Broad/SPARC
Patrick Kleyn
The problem of drug toxicity
>2x106 ADR hospitalizations in 30 years Cost of millions Drug development impediment
Vioxx, troglitazone etc etc etc Genetic variation known
VKORC1, CYP2D6, CYP3A4, CYP3A5 Would be nice to know before unleashing on
population!
Function of variation
Catalog of variation HapMap
Lots of perturbations screening libraries
Unified assay HT, molecular... expression?
Lots of individuals Tissue access
Questions
Can we use mice as a pharmacogenetic discovery tool? Can we identify molecular signatures of response
using inbred mice? Are they heritable; can we map determinants?
Can we recapitulate live animal responses in vitro?
Can we use surrogate tissues (blood)?
Drug
Mouse inbred strain
Liver and serum
Reagents
APAP 5-FU Rapamycin Lovastatin Cyclopamine
129S1/SvImJ A/J AKR/J BALB/cByJ C3H/HcJ C57Bl/6J DBA/2J NOD/LtJ
Specific Goals of Pilot Phase I
Establish dosage levels for 5 drugs in one strain Determine response variations
Serum biomarkers Histology Expression profiling
Phase II Assay responses in 8 strains
Biomarkers, expression profiling, metabolite profiling
Specific Goals of PilotPhase I
Establish dosage levels for 5 drugs in one strain Determine response variations
Serum biomarkers Histology Expression profiling
Phase II Assay responses in 8 strains
Biomarkers, expression profiling, metabolite profiling
AST in congenic B6/A strains (Jax)
In progress...
Three further strain comparisons Transcriptional and metabolic profiling Peripheral blood profiling in vitro hepatocyte assays